Carbamates of 11-hydroxy-10,5(iminomethano)dibenzocyclohepten-13-ones and intermediates thereof



United States Patent CARBAMATES OF 11-HYDROXY-10,5(IMINOMETH- ANO)DIBENZOCYCLOHEPTEN-13-ONES AND IN- TERMEDIATES THEREOF Martin A.Davis, Montreal, Quebec, and Thomas A. Dobson, St. Laurent, Quebec,Canada, assignors to American Home Products Corporation, New York, N.Y.,a corporation of Delaware No Drawing. Filed Feb. 8, 1967, Ser. No.614,548

Int. Cl. C07d 41/08 US. Cl. 260-2393 3 Claims ABSTRACT OF THE DISCLOSUREThere are disclosed herein the compoundsll-carbamoyloxy-12-methy1-10,5(iminomethanol) 10,11 dihydro-5H-dibenzo[a,d]-cyclohepten 13 one, as well as the corresponding 11 Nmethyl, 11-N,N-dimethyl, 11-N- ethyl, 11-N-propyl, 11N-benzyl, 11 N pchlorophenethyl-, carbomayloxy-12-methyl, l2-ethyl, 12-propyl, 12-butyl, 12-amyl, 12-ally1, 12-benzyl, 12-phenethyl, and 12- (3,4,5trimethoxy)phenethyl 10,5 (iminomethano)- 10,11 dihydro 5Hdibenzo[a,d]cyclohepten-5-ones, and the corresponding 11-pyrrolidino-,11-piperidino-, 11- morpholino-, and 11 N ethylpiperazino carbonyloxy-12-methyl, 12-ethyl, 12-propyl, 12-butyl, 12-amyl, 12- allyl, 12-benzyl,12-phenethyl, and 12 (3,4,5 trimethoxy)-phenethyl 10,5(iminomethano)10,11-dihydro- SH-dibenzo[a,d]cyclohepten-5-ones. The compounds areuseful as trichomonicidal, antibacterial and anti-inflammatory agents.

This invention relates to novel chemical compounds having usefulbiological properties. More particularly, this invention relates tonovel carbamates of 11-hydroxy-10,5-(iminomethano)-dibenzocyclohepten-13-ones of the following FormulaI:

wherein R represents a lower alkyl group containing from 1 to 6 carbonatoms, or an aralkyl or substituted aralkyl group containing from 7 to11 carbon atoms, such as, for example, the benzyl, phenethyl,phenylpropyl, or trimethoxyphenethyl, group and R and R representhydrogen, lower alkyl, containing from 1 to 4 carbon atoms, aralkyl, orsubstituted aralkyl, or the grouping NRR taken together may represent aheterocyclic ring optionally containing an additional hetero atom, andcontaining from 4 to 6 carbon atoms, and from 1 to 2 hetero atoms;exemplary of such heterocycles are the pyrrolidino, piperidino,mopholino, and N'-ethylpiperazino rings.

The novel compounds of Formula I may be secured ice from thecorresponding 11-hydroxy-12-substituted -10,5-(iminomethano)-10,1l-dihydro 5H dibenzo[a,d]cyclohepten-13-ones ofFormula II, wherein R is as defined above, by treatment with an arylchloroformate, preferably phenyl chloroformate, in the presence of anacidbinding reagent, preferably an organic amine such as, for example,pyridine. This serves to furnish an ll-aryloxycarbonyloxy 12substituted-10,5(iminomethano)- 10,11 dihydroSH-dibenzo[a,d]cyclohepten-13-one of Formula III, wherein R is asdefined above. This intermediate phenylcarbonate ester is then treatedwith ammonia or an organic amine of the Formula R R NH, wherein R and Rare as defined above. The reaction may be conveniently carried out inthe presence of an inert solvent such as, for example, anhydrous etheror tetrahydrofuran, at a temperature of from 30 to 50 C., and furnishesthe desired carbamate ester of Formula I. This general procedure for theconversion of alcohols to their corresponding carbamates and substitutedcarbamates has been described by W. M. McLamore et al. in J. Org. Chem.,20, 1379 (1955).

The requisite starting materials, viz., the ll-hydroxy-12-substituted-10,5(iminomethano)10,11 dihydro 5H-dibenzo[a,d]-cyclohepten 13 ones of Formula II, are convenientlyprepared as disclosed in our copending US. patent application S.N.552,3-87 filed May 24, 1966, now US. Patent No. 3,426,015. Briefly, thisprocess involves the addition of one molar proportion of bromine to asolution, in an inert solvent, of5H-dibenzo[a,d]cycloheptene-S-carboxamide, prepared as described by M.A. Davis et al. in J. Med. Chem. 7, 88 (1964). The intermediate bromocompound thus produced is heated in a boiling alkanol or water thusgiving 11 bromo 10,5- (epoxymethano) 10,11dihydro-SH-dibenzo[a,d]cyc1ohepten-13-one. This, in turn, is then heatedwith an excess of an organic amine of the Formula RNH wherein R is asdefined above, at elevated temperatures Within the range of IUD- 0, thusfurnishing the desired compounds of Formula II.

The novel compounds of Formula I of this invention have usefulbiological properties and are of value as medicaments. In particular,they have activity against the parasitic organism Trichomonas vaginalisand are tridomonacidal agents. For this purpose they may be formulatedwith suitable excipients as vaginal inserts or vaginal suppositorieseach containing from 50 to 500 mg. of the active ingredient, and may beadministered twice to four times daily, for periods of time of from twoto four weeks. In addition, the compounds have activity against a numberof gram-positive and gram-negative microorganisms and are antibacterialagents. They are effective against certain gram-positive andgram-negative organisms, such as, for example, Staphylococcus pyogenes(both penicillin-sensitive and penicillin-resistant strains), Sarcinailater, St reptococcus jaecalis, Echerichia coli, Aerobacter aerogenes,Salmonella pullorum, Pseudomonas aeruginosa, Proteus mirabilis, andProteus vulgarz's. They may be administered topically to the skin in theform of lotions, ointments or creams containing suitable excipients andfrom 0.1 to 1% of the active ingredient. The compounds also haveactivity against the parasitic organism horse strongyles and areanthelmintic agents. Furthermore, the compounds have anti-inflammatoryaction, and are anti-inflammatory agents which may be used topically asdescribed above.

The following formulae and descriptive examples will illustrate ourinvention, without however, limiting it there- CSIISQCOCJ. C5351! 2 a iN \RQ L EXAMPLE 1 11 phenyoxycarbonyloxy-12-methyl-1O,5(iminornethano)10,11 dihydro H dibenzo[a,d]cyclohepten-13-one (III, R=CH A solution ofl1-hydroxy-12-rnethyl-10,5(iminomethano) 10,11dihydro-SH-dibenzo[a,d]cyclohepten-l3- one (5.0 g., 0.02 mole) andphenyl chloroformate (4.3 g., 0.027 mole) in dry pyridine (50 ml.) isheated under reflux for 1-8 hours. The cooled solution is added to waterand extracted with benzene. The organic layer is, in turn, extractedwith hydrochloric acid followed by water, and is then dried andconcentrated in vacuo. The residual material is recrystallized fromethanol to furnish 3.4 g. of the. title product with M.P. 183-185 C.Elemental analysis confirms the empirical formula C H NO In a similarmanner to that described above, but substituting thel1-hydroxy-12-rnethy1-10,5(irninomethano)-l0,1'1-dihydro-5H-dibenzo[a,d] cyclohepten-13-one, by 11-hydroxy-lZ-ethyl, 11-hydroxy-l2-propyl, 1l-hydroxy-12- butyl, 11 hydroxyl2 amyl, l1 hydroxy 12 allyl,

11 hydroxy 12 benzyl, 11 hydroxy 12 phenethyl, or 11 hydroxy 12(3,4, 5trimethoxy)phenethyl 10,5.(iminomethano) 10,11 dihydro 5H-dibenzo[a,d]cyclohepten 13-ones, the corresponding ll-phenoxycarbonyloxy-lZ-ethyl,l2-propy1, l2-butyl, 12-arnyl, l2-ally1, 12 benzyl, l2-phenethyl, or12-(3,4,5-trimethoxyphen ethyl) 10,5 (iminomethano)10,11-dihydro-5H-dibenzo [a,d]cyclohepten-l3-ones are obtained.

EXAMPLE 2 11 carbamoyloxy 12-methyl-10,5-(iminomethano)-10, 11 dihydroSH-dibenzo[a,d]cyclohepten-13-one (I, R=CH R =R =H) In a similar mannerto that described above, but substituting the 11 phenoxycarbonyloxy 12methyl 10,5

if 000C635 (iminomethano) 10,11dihydro-5H-dibenzo[a,d]cyclohepten-lS-one by the correspondingll-phenoxycarbonyloxy-lZ-ethyl, ll-phenocarbonyloxy 12 propyl,ll-phenoxycarbonyloxy 12 butyl, 1l-phenoxycarbonyloxy-l2- arnyl,ll-phenoxycarbonyloxy 12 allyl, ll-phenoxycarbonyloxy- 1 2-benzyl, 1l-phenoxycarbonyloxyl Z-phenethyl; or1l-phenoxycarbonyloxy-l2(3,4,5-trimethoxy)-phenethyl-10,5-(iminomethano)10,11 dihydro-SH-dibenzo [a,d]cyclohepten-5-ones, and substituting theammonia by methylamine, dimethylamine, ethylarnine, propylamine,benzylamine, p-chlorophenethylamine, pyrrolidine, piperi dine,morpholine, or N-ethylpiperazine, the ll-N-rnethyl, N,N-dimethyl,N-ethyl, N-propyl, N-benzyl,N-p-chlorophenethyl-carbamoyloxy-l2-rnethyl, l2-ethyl, 12- propyl,12-butyl, 12-aniyl, 12-allyl, 12-benzyl, IZ-phenethyl, or12-(3,4,Strimethoxy)phenethyl 10,5 (iminomethano)-10,11-dihydro-5H-di-benzo[a,d]cyclohepten-S-ones are obtained, as wellas the corresponding 1l-pyrrolidino-, 11- piperidino-, 11-morpholino-,and 11 N ethylpiperazino carbonyloxy-lZ-methyl, 12-ethyl, 12-propyl,12-butyl, 12- arnyl, l2-allyl, 12-benzyl, 12-phenethyl, or 12-(3,4,5-trimethoxy)phenethyl-10,5-(irninomethano)-10,1l dihydro- 5H-dibenzo[a,d]cyclohepten-S-ones.

We claim: 1. A compound of the formula M; w t

wherein R is selected from the group which consists of lower alkyl,allyl, benzyl, phenethyl, and (3,4,S-trimethoxy)phenethyl; and wherein Rand R are selected from the group of paired radicals which consists ofhydrogen and hydrogen; hydrogen and methyl; methyl and methyl; hydrogenand ethyl; hydrogen and propyl; hydrogen and benzyl; and hydrogen andpchlorophenethyl; or wherein the grouping NR R is a heterocyclic radicalselected from the group which consists of pyrro1idin0,.piperidino,morpholine and N-ethylpiperazine.

2. 11 carbamoyloxy-12-methy1-10,5-(iminomethano)- 10,11 dihydro 5Hdibenzo[a,d]cyc10hepten-13-one, as claimed in claim 1.

3. 11 phenoxycarbonyloxy 12 methyl-10,5(iminomethano)10,11dihydro-5H-dibenzo[a,d] cyclohepten-13- one.

References Cited UNITED STATES PATENTS 3,412,085 11/1968 Dobson et a1260--239.3

6 OTHER REFERENCES McLamore et al.: J. Org. Chem, vol. 20, pp. 1379-1382 (1955).

5 NORMA S. MILESTONE, Primary Examiner R. T. BOND, Assistant ExaminerUS. 01. X.R.

'zg g UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 35 9, 13 4 Dated April 28 1970 1 r( Martin A. Davis and Thomas A. DobsonIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

j Column 1 line 20 "carbomayloxy" should read carbamoyloxy.

Column 2 line 55 "luter" should read lutea.

Column 3 line 75 "elements" should read elemental Formula III should becorrected:

OCOC H should read 0 t H 0 III 6 5 I 0 III.

SIGNED AND SEALED si s-19m 4 A test:

sa member, mm 1:. 60mm, .111. Anew-g Officer Commissioner of Patents

